Techniques for selecting signal delivery sites and other parameters for treating depression and other neurological disorders, and associated systems and methods

ABSTRACT

The present disclosure is directed generally to techniques for selecting signal delivery sites and other signal delivery parameters for treating depression and other neurological disorders. A method in accordance with a particular embodiment includes obtaining first imaging information corresponding to a first region of a patient&#39;s brain, the first imaging information being based at least in part on functional characteristics of the first region. The method includes obtaining second imaging information corresponding to a second region of the patient&#39;s brain, the second region being a subset of the first region, the second imaging information being based at least in part on functional or structural characteristics of the second region. A target neural population is selected based in part on the second imaging information. The method still further includes applying an electromagnetic signal to the target neural population to improve a patient function.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/395,257, filed Feb. 27, 2009, now U.S. Pat. No. 8,262,714, whichclaims the benefit of U.S. Provisional Application No. 60/086,199, filedAug. 5, 2008, the disclosures of which are fully incorporated herein byreference for all purposes.

TECHNICAL BACKGROUND

Aspects of the present disclosure are directed generally towardtechniques for selecting signal delivery sites and other signal deliveryparameters for treating depression and other neurological disorders, andassociated systems and methods.

BACKGROUND

A wide variety of mental and physical processes are controlled orinfluenced by neural activity in particular regions of the brain. Forexample, the neural functions in some areas of the brain (i.e., thesensory and motor cortices) are organized according to physical orcognitive functions. Several areas of the brain appear to have distinctfunctions in most individuals. In the majority of people, for example,the areas of the occipital lobes relate to vision, the regions of theleft inferior frontal lobes relate to language, and particular regionsof the cerebral cortex appear to be consistently involved with consciousawareness, memory, and intellect.

Many problems or abnormalities can be caused by damage, disease and/ordisorders in the brain. Disorders include neuropsychiatric and/orneuropsychological disorders, such as major depression. A person'sneuropsychiatric responses may be controlled by a looped signal pathbetween cortical structures, e.g., superficial structures at theprefrontal cortex of the brain, and deeper neural populations.

Neurological problems or abnormalities are often related to electricaland/or chemical activity in the brain. Neural activity is governed byelectrical impulses or “action potentials” generated in neurons andpropagated along synaptically connected neurons. When a neuron is in aquiescent state, it is polarized negatively and exhibits a restingmembrane potential typically between −70 and −60 mV. Through chemicalconnections known as synapses, any given neuron receives excitatory andinhibitory input signals or stimuli from other neurons. A neuronintegrates the excitatory and inhibitory input signals it receives, andgenerates or fires an action potential when the integration exceeds athreshold potential. A neural firing threshold, for example, may beapproximately −55 mV.

When electrical activity levels at either the superficial corticalstructure or the deep brain structure are irregular, action potentialsmay not be generated in the normal manner. For example, actionpotentials may be generated too frequently, or not frequently enough.Such irregularities can result in a neuropsychiatric disorder. Itfollows, then, that neural activity in the brain can be influenced byelectrical energy supplied from an external source, such as a waveformgenerator. Various neural functions can be promoted or disrupted byapplying an electrical current to the cortex or other region of thebrain. As a result, researchers have attempted to treat physical damage,disease and disorders in the brain using electrical or magneticstimulation signals to control or affect brain functions.

Transcranial electrical stimulation (TES) is one such approach thatinvolves placing an electrode on the exterior of the scalp anddelivering an electrical current to the brain through the scalp andskull. Another treatment approach, transcranial magnetic stimulation(TMS), involves producing a magnetic field adjacent to the exterior ofthe scalp over an area of the cortex. Yet another treatment approachinvolves direct electrical stimulation of neural tissue using implanteddeep brain stimulation electrodes (DBS). However, the foregoingtechniques may not consistently produce the desired effect with thedesired low impact on the patient. For example, TES may require highcurrents to be effective, which may cause unwanted patient sensationsand/or pain. TMS may not be precise enough to target only specific areasof the brain. Deep brain stimulation is a relatively invasive procedure,and it can be relatively difficult to implant DBS electrodes in tissuelocated well below the cortex. Accordingly, there exists a need forproviding more effective, less invasive treatments for neuropsychiatricand neuropsychological disorders.

BRIEF SUMMARY

FIG. 1 is a flow diagram illustrating a method for treating a patient inaccordance with a particular embodiment of the disclosure.

FIG. 2 is a schematic illustration of cortical and sub-cortical brainstructures, along with regions selected in accordance with embodimentsof the disclosure.

FIG. 3 is a flow diagram illustrating a method for treating a patient'sdepression in accordance with an embodiment of the disclosure.

FIG. 4 is a partially schematic illustration of brain and peripheralstructures that may be associated with the method shown in FIG. 3.

FIG. 5 illustrates an electrode device operatively coupled to anexternal controller in accordance with an embodiment of the disclosure.

FIG. 6 is a schematic illustration of a pulse system configured inaccordance with several embodiments of the disclosure.

FIG. 7 is an isometric illustration of an electrode device that carriesmultiple electrodes in accordance with an embodiment of the disclosure.

FIGS. 8A-8C are partially schematic illustrations of electrode devicesimplanted at locations selected in accordance with embodiments of thedisclosure.

DETAILED DESCRIPTION Introduction

The present disclosure is directed to methods for treating neurologicdysfunction, which may include neuropsychiatric, neuropsychological,neurodevelopmental and/or other disorders, and associated systems forcarrying out such methods. As used herein, the phrase “neurologicdysfunction” is used to encompass a variety of conditions or disorders,including neuropsychiatric disorders and neuropsychological disorders.As a further shorthand, the term “neuropsychiatric disorders” is used toinclude both neuropsychiatric disorders and neuropsychologicaldisorders. Representative types of disorders falling within thisdefinition include major depression, mania and other mood disorders,bipolar disorder, obsessive-compulsive disorder (OCD), Tourette'ssyndrome, schizophrenia, dissociative disorders, anxiety disorders,phobic disorders, post-traumatic stress disorder (PTSD), borderlinepersonality disorder, as well as others such as AttentionDeficit/Hyperactivity Disorder (ADHD) and/or craving or reward drivenbehaviors (e.g., associated with an addiction to legal or illegal drugs,gambling, sex, or another condition such as obesity).

In general, various aspects of the methods and systems disclosed hereinare directed to treating neurological conditions or states withelectromagnetic stimulation, typically electrical stimulation applied toparticular cortical structures of the patient's brain, e.g., from anepidural or subdural location. As used herein, “stimulation” refersgenerally to extrinsic signals directed to the patient to achieve abeneficial result. The signals may have an inhibitory or excitatoryeffect on particular neural populations. One representative techniqueincludes using at least two sets of imaging information to moreparticularly identify the neural population to which therapeuticelectromagnetic signals are delivered. Another particular method,directed to depressed patients, can include applying electromagneticsignals to one or more patient brain regions expected to correspond tothe dorsolateral prefrontal cortex (DLPFC) and identifying a change in aregion of the brain other than the DLPFC. Based at least in part uponthis information, a practitioner can determine whether or not thepatient is a candidate for cortical signal delivery to addressdepression, and/or the practitioner can select a target neuralpopulation to receive cortical signals, and/or the practitioner canupdate cortical signal delivery parameters. Further particularembodiments are described in greater detail below with reference toFIGS. 1-8C.

Systems and Methods for Patient Selection, Target Neural PopulationSelection, and Signal Delivery Selection

FIG. 1 is a flow diagram illustrating a process 100 for treating apatient in accordance with a particular embodiment of the disclosure.The process 100 includes obtaining first imaging informationcorresponding to a first region of a patient's brain, with the firstimaging information being based at least in part on functionalcharacteristics of the first region (process portion 101). For example,the first imaging information can be obtained using functional magneticresonance imaging (fMRI) techniques. Process portion 102 can includeobtaining second imaging information corresponding to a second region ofthe patient's brain, with the second region being a subset of the firstregion. The second imaging information can be based at least in part onfunctional or structural characteristics of the second region, and canhave a resolution greater than that of the first imaging information.Accordingly, the second information can be used to more preciselyidentify a target neural population that will receive therapeuticelectromagnetic signals. For example, a typical fMRI-based process forlocating a target neural population has a resolution of about 1-3centimeters. By adding the second information, (e.g., using diffusiontensor imaging processes described later) the practitioner can achieve aresolution of 3 millimeters or less. In addition to increasedresolution, the foregoing technique can be conducted without a surgicalprocedure and is therefore less invasive than other techniques. Stillfurther, this technique can be readily used to identify target neuralpopulations of “silent” neurons, e.g., cognitive, emotive and/or otherneurons that typically do not produce an immediate motor or sensoryresponse.

The practitioner can use the first and/or second information to identifyparticular areas of interest, and/or to eliminate from furtherconsideration areas that are not of interest. In any of these cases,process portion 103 includes selecting a target neural population basedat least in part on the second imaging information, and process portion104 includes applying an electromagnetic signal to the target neuralpopulation to improve a patient function. For example, this techniquecan be used to improve the functioning of a patient suffering fromdepression. A representative example is described in further detailbelow with reference to FIG. 2.

FIG. 2 is a schematic illustration of a patient's brain 220 illustratingcortical structures 221 (e.g., superficial or outer structures) locatedat the cortex 223, and sub-cortical structures 222 (e.g., deeper,non-superficial structures) located below or within the cortex 223. Thecortical structures 221 can include the dorsolateral prefrontal cortex(DLPFC) 224 which has neuronal tracts (illustrated schematically bydoubled-headed arrows in FIG. 2) extending to the sub-corticalstructures 222. The DLPFC has connections with many sub-corticalstructures 222 but for purposes of illustration, Brodmann area 10 andBrodmann area 25 are specifically shown in FIG. 2. In a particularembodiment, the practitioner can preferentially focus imaging tasks onone or brain locations expected to form a portion of or correspond tothe DLPFC and then preferentially direct electromagnetic signals toportions of the DLPFC. In other embodiments, the practitioner can focusimaging tasks (and electromagnetic signals) on particularneuroanatomical structures, portions of which may be included in theDLPFC, e.g., portions of the patient's middle frontal gyrus, and/orsuperior frontal gyrus. In still further embodiments, the practitionercan focus imaging tasks (and/or electromagnetic signals) on still otherstructures, e.g., the patient's inferior frontal gyrus, orbitofrontalcortex, and/or ventrolateral prefrontal cortex. Additional details oftechniques for targeting and applying therapy to these structures areincluded in pending U.S. application Ser. No. 12/330,437, filed Dec. 8,2008 and incorporated herein by reference.

The DLPFC 224 can include subareas, for example, a cognitive area 225associated with the patient's cognitive functioning, and an emotive area226 associated with the patient's emotional functioning, both shownschematically in FIG. 2. The locations of these areas may in at leastsome cases vary from patient to patient. In addition, individualpatients may have a depression condition that results from dysfunctionsin the cognitive area 225 or the emotive area 226 or both the cognitivearea 225 and the emotive area 226. Using functional imaging techniques(e.g., fMRI), a practitioner can identify which of the two areas is alikely candidate for cortical stimulation. For example, the patient canbe exposed to a stimulus (described in further detail later) thattriggers an acute depression response, while the patient's brain isimaged. In some cases, only one of the areas 225, 226 may be a suitablecandidate, and in other embodiments, both areas may be suitablecandidates. In any of these cases, the cognitive area 225 and/or theemotive area 226 can correspond to the first region of the patient'sbrain described above with reference to FIG. 1. In still anotherembodiment, neither the cognitive area 225 nor the emotive area 226 mayparticularly stand out when the first imaging information is obtained,and accordingly, the entire DLPFC 224 or some other region of the DLPFCmay correspond to the first region described above with reference toFIG. 1.

As shown in FIG. 2, the cognitive area 225 and the emotive area 226 mayeach have many tracts that descend to a variety of sub-corticalstructures 222. In certain embodiments, the practitioner may beparticularly interested in applying electrical signals to those areas ofthe DLPFC 224 that have a significant number of neuronal fibers ortracts that descend to Brodmann area 10 and/or Brodmann area 25.Accordingly, the practitioner can obtain the second imaging informationdescribed above with reference to FIG. 1 to identify a second, moreprecisely defined region of the patient's brain suitable for receivingcortical stimulation. For example, if the cognitive area 225 is ofparticular interest, the second imaging information can be used toidentify a second region 227 a that includes tracts (or a greater numberof tracts or density of tracts) extending to Brodmann area 25 and/orBrodmann area 10. If the emotive area 226 is of particular interest, thepractitioner can identify a second region 227 b that has tracts (or agreater number of tracts or density of tracts) descending to Brodmannarea 25 and/or Brodmann area 10. Accordingly, the first imaginginformation described above with reference to FIG. 1 can identify ageneral region for cortical stimulation with a first level ofresolution, and the second imaging information can identify one or moresecond regions with a higher level of resolution to more preciselyidentify one or more target neural populations. Further details ofsuitable techniques for obtaining the first imaging information and thesecond imaging information are described below.

In at least some embodiments, the first imaging information is based atleast in part on functional characteristics of the first region. Forexample, the first information can be obtained using correlates that areassociated with or indicative of neural functioning levels. Suchcorrelates include blood flow, metabolism, perfusion, glucose levels,water levels, magnetic characteristics, and/or electricalcharacteristics. Suitable techniques for identifying and/or measuringsuch correlates can include fMRI, spectroscopy based on MRI, positronemission tomography (PET), single photon emission computed tomography(SPECT), and/or computed tomography (CT). In any of these embodiments,the image or information used to produce the image is correlated with aparticular activity related to the patient's depression. For example, insome cases, the patient's working memory is affected by depression andaccordingly, the patient can undertake working memory tasks while thefirst imaging information is collected. In other embodiments, thepatient can be exposed to emotion-triggering stimuli (e.g., visual,auditory, tactile and/or olfactory stimuli) so as to identify regions ofthe brain that are active in response to such stimuli and are correlatedwith the patient's depression. Further details associated with assessingpatient functioning are included in co-pending U.S. Patent PublicationNo. US 2008/0103548, incorporated herein by reference.

The second imaging information can be structural or functional in natureand is generally obtained for a smaller region of the brain (e.g., asubset of the first region) than is the first imaging information. In aparticular embodiment, diffusion tensor imaging (DTI) techniques areused to identify neuronal tracts or fibers descending to sub-corticalareas that are known or expected to play a role in the patient'sdepression. More specifically, the practitioner can identify a “seedpoint” at the DLPFC using the first information. On the basis of theseed point, the practitioner can perform a fiber tracking analysis toidentify fibers that connect the DLPFC to specific sub-corticalstructures. This technique can be performed for multiple seed points atthe DLPFC, and one or more target neural populations can be selected toinclude the areas of the DLPFC having the highest density of (intact)fiber tracts that descend to the specific sub-cortical area(s) ofinterest. Accordingly, the foregoing tractography analysis can apply towhite matter in the brain, in contrast to techniques that may apply onlyto gray matter.

The foregoing approach is expected to produce better (e.g., moreefficacious) results than identifying and stimulating a deep brainstructure because many deep brain structures have a high density oftracts that extend to many different superficial locations, some ofwhich may be associated with the patient's depression, and many of whichare not. As a result, methods that focus on stimulating deep brain areasmay be inefficient and/or may create unintended cortical effects becauseit may be difficult to accurately target the deep brain area(s) ofparticular interest. Accordingly, in particular embodiments of thepresent techniques, no deep brain stimulation is applied. In a furtherparticular aspect of this embodiment, simulation is applied only toareas identified based on the second imaging information. Furtherinformation relating to the use of DTI for site identification isincluded in U.S. Patent Publication No. US 2008/0039895, incorporatedherein by reference.

In general terms, DTI techniques identify neuronal tracts by identifyingadjacent tissue volumes (voxels) having diffusion tensors aligned in thesame direction. In addition to or in lieu of using diffusioncharacteristics to identify tracts, the practitioner can use diffusioninformation to identify the level of anisotropy of the brain tissue,typically referred to as fractional anisotropy (FA). In general terms,FA refers to the magnitude of the diffusion tensor, as opposed to itsdirection. It is expected that in at least some embodiments, the levelof anisotropy can be indicative of regions affected by depression. Forexample, if the FA level for a particular region of the DLPFC isrelatively low (e.g., lower than a standard or average value across ageneral patient population), this can indicate an area associated withthe patient's depression. If the FA level is low, yet still above athreshold value, this may indicate an area suitable for corticalstimulation. Accordingly, the FA level can be used to identify patientswho are suitable candidates for cortical stimulation therapy, and/ortarget neural populations in patients who are suitable candidates.Suitable threshold FA values are expected to be different for differentbrain areas and/or different neuropsychiatric/neuropsychologicalconditions. FA values may also be used to identify changes (e.g.,improvements) in patient condition over time, as a result of thetherapeutic treatments described herein. For example, it is expectedthat the patient's FA values may increase as a result of structuralchanges, including but not limited to dendritic sprouting and/or theformation of new axons.

In other embodiments, functional characteristics of the brain may beused to identify the second region described above with reference toFIG. 1. For example, spectroscopy may be used. In a particular aspect ofthis embodiment, the practitioner can analyze fMRI results on areal-time or nearly real-time basis, and conduct a magnetic resonancespectroscopy (MRS) diagnosis on a subset region of the brain in a singlepatient visit. When the practitioner uses spectroscopy to obtain thesecond information, the practitioner can focus the analysis on a smallerarea than may be used to obtain the first information, resulting in ahigher sensitivity analysis and an expected increase in the precision ofthe results.

Techniques other than spectroscopy may also be used to identify thesecond brain region, based on structural characteristics of the brain.For example, the thickness of the gray matter within the first regioncan be used to identify the second region. In a particular embodiment,the gray matter thickness is assessed using MRI techniques. In general,the greater the gray matter thickness, the greater the functionality ofthe tissue. The practitioner can select highly functional tissue as thetarget neural population in cases for which it is expected that thiswill be beneficial, e.g., when it is expected that stimulation willencourage the functional tissue to take on additional functionality. Thepractitioner can select less functional tissue in cases for which it isexpected that stimulation can raise the functionality to normal orapproximately normal levels. These techniques can be used separately orin combination.

As described above with reference to FIG. 1, once a suitable secondregion has been selected, the practitioner can apply an electromagneticsignal to the target neural population to improve a patient function. Ina particular embodiment, the practitioner uses a cortical electrode(e.g., an electrode positioned epidurally or subdurally within thecranial cavity of the patient's skull, proximate to the target neuralpopulation, and outside a cortical surface of the patient's brain) toapply electrical signals to the target neural population. Depending uponthe patient's condition, the electromagnetic signals may be applied in amanner that inhibits the target neural population, or excites orfacilitates the target neural population. The frequency and/or polarity(anodal or cathodal) of the signal may be selected to achieve thedesired result. The stimulation may be delivered so as to have a directeffect on the target neural population, for example, an effect thatlasts as long as or slightly longer than the stimulation itself. Inother embodiments, the stimulation may be applied to neural populationsthat are expected to retain long-lasting changes (e.g., neuroplasticchanges) that can last for days, weeks, months or years after thestimulation has ceased. In such cases, the treatment regimen can includean adjunctive therapy in combination with the electrical stimulation.Representative adjunctive therapies include working memory tasks,exposure to emotional triggers, psychological counseling and others.

In other embodiments, techniques generally similar to the foregoingtechniques can be used to perform functions other than identifyingsuitable target neural populations. For example, such techniques can beused to screen treatment candidates. In a particular embodiment, if thepatient's FA level is low, the patient may be a suitable candidate forcortical stimulation treatment. However, if the FA level is too low, thepatient may not respond adequately to cortical stimulation and mayaccordingly be screened out or selected for an alternative treatment.

In another embodiment, one or more of the foregoing techniques can beused to select a particular treatment modality. For example, if thepatient's FA value is within a particular range, the patient may beselected to undergo cortical stimulation. If the FA value is within adifferent range, the patient may be expected to respond better totranscranial magnetic stimulation (TMS) techniques, or deep brainstimulation (DBS) techniques. Accordingly, the particular technique ormodality used to treat the patient can depend upon the patient's FAvalue.

In still further embodiments, the FA value may change over the course oftime and/or during the course of treatment. Accordingly, the foregoingtechniques may be applied at additional points during the patient'streatment regimen to update the signal delivery location and/or thetreatment modality used to affect neurons at the target location. Any ofthe foregoing techniques may also be used to select or update signaldelivery parameters other than the target neural population. Suchparameters can include the signal frequency, amplitude (voltage and/orcurrent), polarity (anodal or cathodal) and/or delivery mode (e.g.,unipolar or bipolar).

Other techniques may be used in addition to the foregoing techniques tonot only identify the target neural population, but identify one or moreelectrode locations that are expected to deliver signals to the targetlocation in a particular (e.g., efficient) manner. For example, apractitioner can use numerical simulation techniques in combination withstructural MRI data to estimate the conductivity of the region aroundthe target neural population. Such techniques typically use thedifferent electrical characteristics of different substances andstructures in the brain (e.g., cerebral spinal fluid, neurons,connective tissue, vascular structures and others) to estimate theconductivity of different electrical paths. The practitioner can thenselect the position of a cortical electrode to be one that results inthe shortest and/or lowest conductivity path to the target neuralpopulation. It is expected that such an arrangement can reduce the powerrequired to deliver signals to the target neural population, and canaccordingly provide stimulation for a greater period of time before itbecomes necessary to replace or recharge the power supply that powersthe electrodes. This approach can also reduce or eliminate thepossibility of misdirected current creating unintended effects atpopulations other than the target neural population. Similar techniquesmay also be used to aid the practitioner in aligning the electric fieldlines generated by one or more electrodes with anatomical features. Forexample, these techniques can be used to align field lines with theaxons of neurons at the target neural population.

FIG. 3 is a flow diagram illustrating a process 300 in accordance withanother embodiment of the disclosure. The process 300 can make use ofnaturally occurring connections between the patient's DLPFC and otherareas of the patient's brain to provide information that is then used toscreen the patient, identify a target neural population, and/or updatesignal delivery parameters. In a representative example, once a patientis identified as having depression or anotherneuropsychological/neuropsychiatric disorder (process portion 301), thepractitioner can identify a baseline level of excitability for a firstarea of the patient's brain that does not include the patient's DLPFC.For example, the first area of the patient's brain can include thepatient's motor cortex or sensory cortex. Process portion 303 includesperforming several functions for at least one second area of thepatient's brain, located at the patient's DLPFC. These functions caninclude applying stimulation to the patient's DLPFC (process portion305) and, after applying stimulation to the patient's DLPFC, identifyinga change in the patient's excitability level at the first area of thebrain (process portion 306). Based at least in part on the identifiedchange in the patient's excitability level at the first area, processportion 307 can include performing any of the following functions:identifying the patient as a candidate for cortical signal delivery(process portion 309), selecting a target neural population to receivecortical signals (process portion 310), and/or updating cortical signaldelivery parameters (process portion 311). A representative exampleimplementing an embodiment of the process 300 shown in FIG. 3 isdescribed below with reference to FIG. 4.

FIG. 4 is a partially schematic illustration of a portion of thepatient's brain 220, identifying the DLPFC 224 and cortical, non-DLPFCbrain areas with which the DLPFC 224 communicates. These areas caninclude the motor cortex 230 and the sensory cortex 231, among others.The motor cortex 230 communicates with one or more of the patient'smuscles 233 (e.g., at the patient's arm or hand) via the spinal cord232. The sensory cortex 231 communicates with one or more of thepatient's sensory receptors 234 (e.g., the patient's olfactory nerve).In some cases, e.g. for tactile sensory receptors at the patients trunkor extremities, this communication also occurs via the spinal cord 232.In a representative procedure, the practitioner identifies a baselinelevel of excitability of the patient's motor cortex, for example, byassessing the patient's response to motor stimuli. The practitioner canthen apply excitatory or inhibitory stimuli to the DLPFC 224. Forexample, the practitioner can apply rTMS signals to the patient for aperiod of about 20 minutes. After stimulating the DLPFC 224, thepractitioner can again assess the patient's level of motor excitability,for example, by applying single-pulse and/or paired-pulse signals (e.g.,TMS signals) to the patient's brain and assessing the response level.Single pulse TMS signals may be used to assess a direct effect of theDLPFC on the patient's level of motor excitability, and paired-pulse TMSsignals may be used to isolate the effect of inhibitory and/orexcitatory interneurons on the patient's level of motor excitability. Inany of these embodiments, the foregoing procedure can be repeated formultiple sites at the DLPFC 224, and one or more of these sites can beselected as a target neural population, based upon the effect thatstimulation at the site has on the patient's level of motorexcitability.

In particular embodiments, it is expected that locations of the DLPFC224 that have a greater effect on motor excitability than others may besuitable candidates for cortical stimulation. Similar techniques can beused to optimize and/or update the signal delivery parameters used toprovide therapy to the patient, after a cortical stimulation device hasbeen implanted in the patient. For example, the effect of thestimulation on the patient's motor excitability at a variety ofparameter settings (e.g., stimulation amplitude, polarity, and/orfrequency) can be determined and, based upon this determination,particular parameters can be selected or eliminated. The same or asimilar technique can be used during the course of the patient's therapyto update signal delivery parameters, for example, as the patient's bodyadapts to the applied therapy, and/or as the functional level of thetarget neural population changes as a result of therapy.

Many aspects of the foregoing process can be automated in certaininstances. For example, once the patient has received a corticalimplant, the patient can also receive one or more implanted sensorslocated at the motor cortex or sensory cortex, or at the patient's spine(e.g., at a cervical location), or at a peripheral location (e.g., atthe patient's muscle or sensory receptor). The sensor(s) can identifychanges in the level of excitability at any of these locations and canbe coupled to a controller which is in turn coupled to electrodesimplanted at the DLPFC. Accordingly, the controller can automaticallyadjust the signal delivery parameters applied to the electrodes at theDLPFC as the patient's responses to therapeutic signals (or testsignals) provided by the electrodes change. This closed-loop arrangementcan operate in a semi-automated or fully automated manner to reduce oreliminate the need for the patient or the practitioner to continuouslymonitor patient performance and/or response to the therapy.

In many instances, it is desirable to compare the state of a patientwhen the patient is acutely depressed, to a baseline state of thepatient. This technique can be used to identify areas of the brain thatare active or inactive when a patient is depressed. For example, thepractitioner can obtain an image of the patient's brain when the patientis acutely depressed, and compare that image with one obtained when thepatient is in a stable or baseline condition. This technique can be usedto identify the first region of the brain described above with referenceto FIG. 1, or, in particular embodiments (assuming a high degree ofresolution), this technique can be used to identify the second region.In any of these cases, the practitioner will obtain an image of thepatient's brain or the relevant portion of the patient's brain when thepatient is in the baseline or first state, then acutely affect thepatient's emotional or cognitive functioning, obtain a second imagewhile the patient is in the second state, and compare the images.

A variety of techniques are expected to be suitable for creating such aneffect. For example, rapid tryptophan depletion, which is presently usedto identify depression patients suitable for SSRI treatments, can beused to trigger an acute depression condition. Sleep deprivation isanother technique that can acutely modulate depression (e.g., it cancause acute remission of depression symptoms), as is hypnosis. In othercases, a patient can be shown sad pictures to induce sadness,depression, or another emotion. In still further cases, multiplesessions of rTMS can acutely modulate the patient's depression response.For example, rTMS can cause a reduction in depression symptoms, or aremission of depression. A variety of imaging/visualization techniquescan be used to identify brain areas associated with the acute response.These areas may be hypoactive or hyperactive. Such techniques caninclude PET scans based on FDG or water analysis, perfusion MRI,connectivity fMRI, and/or task-related fMRI (e.g., in which a patientperforms a cognitive or memory task).

In particular cases, the DLPFC or portions of the DLPFC are expected tobe hypoperfused and/or hypometabolic when the patient is depressed, andthus a suitable target neural population can be identified usingmeasures of perfusion/blood flow and/or glucose consumption. In othercases, patients with depression or major depressive disorder (MDD) mayhave reduced glutamate, and/or reduced glutamate/glutamine peaks, and/orreduced choline levels at the frontal cortex, the DLPFC, and/or othercortical regions or subregions. Magnetic resonance spectroscopy (MRS) isexpected to be suitable for identifying such areas as target neuralpopulations and/or identifying indications of recovery after therapeutictreatments in accordance with the present disclosure.

In still another embodiment, EEG measurements may be used to identifyareas with increased and/or otherwise perturbed activity. For example,EEG measurements may be used to detect increased gamma and/or theta waveactivity, which is expected to correlate with depression. In particularcases, EEG measurements can detect changes in brain activity induced byrTMS stimulation.

Representative Stimulation System Embodiments

Many aspects of various techniques or procedures described above can beperformed by suitable systems configured to deliver cortical stimulationand, in certain cases, stimulation in accordance with other modalities.FIG. 5 schematically illustrates a representative cortical signaldelivery system 250. The system 250 can include a pulse system 260 thatis positioned external to the patient's skull. For example, as shown inFIG. 5, the pulse system 260 can be placed on the external surface ofthe patient's skull 235, beneath the scalp. In another arrangement, thepulse system 260 can be implanted at a subclavicular location. The pulsesystem 260 can be controlled internally via pre-programmed instructionsthat allow the pulse system 260 to operate autonomously afterimplantation. In other embodiments, the pulse system 260 can beimplanted at other locations, and at least some features of the pulsesystem 260 can be controlled externally. For example, FIG. 5 illustratesan external controller 265 that controls the pulse system 260.

FIG. 6 schematically illustrates details of an embodiment of the pulsesystem 260 described above. The pulse system 260 generally includes ahousing 261 carrying a power supply 262, an integrated controller 263, apulse generator 266, and a pulse transmitter 267. In certainembodiments, a portion of the housing 261 may include a signal returnelectrode. The power supply 262 can include a primary battery, such as arechargeable battery, or other suitable device for storing electricalenergy (e.g., a capacitor or supercapacitor). In other embodiments, thepower supply 262 can include an RF transducer or a magnetic transducerthat receives broadcast energy emitted from an external power source andthat converts the broadcast energy into power for the electricalcomponents of the pulse system 260.

In one embodiment, the integrated controller 263 can include aprocessor, a memory, and/or a programmable computer medium. Theintegrated controller 263, for example, can be a microcomputer, and theprogrammable computer medium can include software loaded into the memoryof the computer, and/or hardware that performs the requisite controlfunctions. In another embodiment identified by dashed lines in FIG. 6,the integrated controller 263 can include an integrated RF or magneticcontroller 264 that communicates with the external controller 265 via anRF or magnetic link. In such an embodiment, many of the functionsperformed by the integrated controller 263 may be resident on theexternal controller 265 and the integrated portion 264 of the integratedcontroller 263 may include a wireless communication system.

The integrated controller 263 is operatively coupled to, and providescontrol signals to, the pulse generator 266, which may include aplurality of channels that send appropriate electrical pulses to thepulse transmitter 267. The pulse transmitter 267 is coupled to a signaldelivery device 240, e.g., an electrode device 241 that carrieselectrodes 242. In one embodiment, each of these electrodes 242 isconfigured to be physically connected to a separate lead, allowing eachelectrode 242 to communicate with the pulse generator 266 via adedicated channel. Accordingly, the pulse generator 266 may havemultiple channels, with at least one channel associated with each of theelectrodes 242 described above. Suitable components for the power supply262, the integrated controller 263, the external controller 265, thepulse generator 266, and the pulse transmitter 267 are known to personsskilled in the art of implantable medical devices.

The pulse system 260 can be programmed and operated to adjust a widevariety of stimulation parameters, for example, which electrodes 242 areactive and inactive, whether electrical stimulation is provided in aunipolar or bipolar manner, signal polarity, and/or how stimulationsignals are varied. In particular embodiments, the pulse system 260 canbe used to control the polarity, frequency, duty cycle, amplitude,and/or spatial and/or topographical qualities of the stimulation.Representative signal parameter ranges include a frequency range of fromabout 0.5 Hz to about 125 Hz, a current range of from about 0.5 mA toabout 15 mA, a voltage range of from about 0.25 volts to about 20 volts(e.g., approximately 10 volts), and a first pulse width range of fromabout 10 psec to about 500 psec The stimulation can be varied to match,approximate, or simulate naturally occurring burst patterns (e.g.,theta-burst and/or other types of burst stimulation), and/or thestimulation can be varied in a predetermined, pseudorandom, and/or otheraperiodic manner at one or more times and/or locations.

In particular embodiments, the pulse system 260 can receive informationfrom selected sources, with the information being provided to influencethe time and/or manner by which the signal delivery parameters arevaried. For example, the pulse system 260 can communicate with adatabase 270 that includes information corresponding to reference ortarget parameter values. Sensors can be coupled to the patient toprovide measured or actual values corresponding to one or moreparameters. The measured values of the parameter can be compared withthe target value of the same parameter. Accordingly, this arrangementcan be used in a closed-loop fashion to control when stimulation isprovided and when stimulation may cease. In one embodiment, someelectrodes 242 may deliver electromagnetic signals to the patient whileothers are used to sense the activity level of a neural population. Inother embodiments, the same electrodes 242 can alternate between sensingactivity levels and delivering electrical signals. In either embodiment,information received from the signal delivery device 240 can be used todetermine the effectiveness of a given set of signal parameters and,based upon this information, can be used to update the signal deliveryparameters and/or halt the delivery of the signals.

In other embodiments, other techniques can be used to providepatient-specific feedback. For example, a detection system or device 280such as a magnetic resonance chamber can provide informationcorresponding to the locations at which a particular type of brainactivity is occurring and/or the level of functioning at theselocations, and can be used to identify additional locations and/oradditional parameters in accordance with which electrical signals can beprovided to the patient to further increase functionality. Accordingly,the system can include a direction component configured to direct achange in an electromagnetic signal applied to the patient's brain basedat least in part on an indication received from one or more sources.These sources can include a detection component (e.g., the signaldelivery device and/or the magnetic resonance chamber 280).

FIG. 7 is a top, partially hidden isometric view of an embodiment of asignal delivery device 740, configured to carry multiple corticalelectrodes 742. The electrodes 742 can be carried by a flexible supportmember 744 to place each electrode 742 in contact with a stimulationsite of the patient when the support member 744 is implanted. Electricalsignals can be transmitted to the electrodes 742 via leads carried in acommunication link 745. The communication link 745 can include a cable746 that is connected to the pulse system 260 (FIG. 6) via a connector747, and is protected with a protective sleeve 748. Coupling aperturesor holes 749 can facilitate temporary attachment of the signal deliverydevice 740 to the dura mater at, or at least proximate to, a stimulationsite. The electrodes 742 can be biased cathodally and/or anodally. In anembodiment shown in FIG. 7, the signal delivery device 740 can includesix electrodes 742 arranged in a 2×3 electrode array (i.e., two rows ofthree electrodes each), and in other embodiments, the signal deliverydevice 740 can include more or fewer electrodes 742 arranged insymmetrical or asymmetrical arrays. The particular arrangement of theelectrodes 742 can be selected based on the region of the patient'sbrain that is to be stimulated, and/or the patient's condition.

FIG. 8A is a schematic illustration of a first electrode device 841 aimplanted above or upon a patient's middle frontal gyrus 236 inaccordance with an embodiment of the disclosure. The first electrodedevice 841 a includes a first electrode 842 a and a second electrode 842b that are carried by a substrate or support member 844. The first andsecond electrodes 841 a, 841 b are coupled to a pulse generator (notshown) in a manner understood by one of ordinary skill in the art. Inthis embodiment, each electrode 842 a, 842 b is generally circular.Depending upon embodiment details, such electrodes 842 a, 842 b can beapproximately 0.5-4.5 mm (e.g., 3.75 mm) in diameter, and can have acenter-to-center spacing of approximately 10-40 mm (e.g., 15 mm, 18 mm,or another separation distance). The centers of the first electrode 842a and the second electrode 842 b can be positioned to approximatelyintersect or reside along or proximate to a line or an arc 243 a thatgenerally bisects at least a portion of the middle frontal gyrus 236into superior and inferior portions. The particular position along line243 a can be determined by any of the foregoing techniques directed toidentifying target neural populations and associated stimulation sites(e.g., electrode placement sites). Such techniques can also be used toplace the electrodes at other cortical locations, including, but notlimited to, those described below with reference to FIGS. 8B-8C.

FIG. 8B is a schematic illustration of a second electrode device 841 bimplanted above or upon a patient's middle frontal gyrus 236 inaccordance with another embodiment of the previously described surgicalimplantation protocol. The second electrode device 841 b includes asupport member 844 that carries a first, a second, and a third electrode842 a, 842 b, 842 c and possibly an nth electrode 842 d, where n isgreater than or equal to 4. In several embodiments, the second electrodedevice 841 b can be positioned such that as many electrodes 842 a-842 das possible reside above, along, or proximate to a line or an arc 243 bthat generally bisects at least a portion of the middle frontal gyrus236 as the line or arc 243 b extends between the middle frontal gyrus236 and the central sulcus 237 in an anterior-posterior direction.

FIG. 8C is a schematic illustration of a third electrode device 841 cimplanted above or upon a patient's middle frontal gyrus 236 inaccordance with yet another embodiment of the aforementioned surgicalimplantation protocol. The third electrode assembly 841 c includes asupport member 844 that carries a first and a second row of electrodes851, 852, where each electrode row 851, 852 includes at least a firstelectrode 842 a and possibly up to an n^(th) electrode 842 d. The thirdelectrode device 841 c can be positioned such that each electrode row851, 852 is approximately equidistant from a line or arc 243 c thatextends anteriorly from the central sulcus 237 and which approximatelybisects a portion of the middle frontal gyrus 236; or such that asuperior and an inferior electrode row 851, 852 are approximatelyequidistant from the superior frontal sulcus 238 and the inferiorfrontal sulcus 239, respectively.

In some embodiments, the electrode device 841 c can include electrodes842 a-842 d that are arranged, organized, or positioned in a curvilinearor arcuate manner rather than in a linear manner. An arc along whichelectrodes 842 a-842 d are positioned can be predefined such that theelectrodes carried by an as-manufactured electrode device will conformor approximate conform to the curvature of a particular portion orsection of a neuroanatomical structure, such as the crown of the middlefrontal gyrus spanning Brodmann areas 9, 46, and/or 9/46.

A stimulation procedure directed toward the application of extrinsicstimulation signals to treat neuropsychiatric dysfunction can includeone or more time periods in which each electrode of a given electrodeassembly is electrically active. Additionally or alternatively, astimulation procedure can include one or more time periods in whichparticular electrode subsets carried by a given electrode assembly areelectrically active. The activation of each electrode and/or one or moreelectrode subsets can depend upon the type of neurologic dysfunctionunder consideration and/or the patient's clinical response, imagingresponse, and/or electrophysiologically measured (e.g., ECoG) responseto the applied stimulation signals.

In a representative example, the electrode device 841 b shown in FIG. 8Bcan have an initially active electrode subset that includes the first,second, and third electrodes 841 a-841 c. Depending upon the natureand/or extent of a patient's response to the extrinsic stimulationsignals (for instance, the presence or absence of a noticeable orfavorable acute response, and/or the presence or absence of a beneficialor adverse response that arises over the course of a number of weeks(e.g., 2-12 weeks)), additional, one or more anterior electrodes 841 dcan be activated at one or more times. Moreover, one or moremost-posterior electrodes 841 a, 841 b can be deactivated at one or moretimes, and/or stimulation signals applied to such more-posteriorelectrodes 841 a, 841 b at a reduced intensity or level in the eventthat clinical, imaging, and/or electrophysiologic data indicates thatsuch electrodes 841 a, 841 b provide relatively less or littlecontribution to therapeutic efficacy.

In a representative embodiment, the third electrode device 841 c shownin FIG. 8C can include any given electrode subset that is active at oneor more times, with active electrodes located in one or both electroderows 851, 852. In certain situations, an initial set or subset ofelectrodes carried by an electrode device can be used to initially applystimulation signals. Depending upon embodiment details, the initial setof electrodes can include some or all of the electrodes carried by theelectrode device. After a first time period during which the patientexperiences a favorable therapeutic response, particular electrodes(e.g., one or more most-posterior electrodes) within the initial set ofelectrodes can be activated at a reduced signal intensity, level, orduration, or deactivated during a second time period, and the patientmonitored to determine whether a sufficiently high or adequate level oftherapeutic benefit is present. Such a stimulation procedure cansuccessively, over time, determine a minimum number of active electrodesthat are useful for achieving or maintaining therapeutic efficacy. Inthe event that therapeutic efficacy changes or degrades over timefollowing a generally stable period of therapeutic benefit, theforegoing stimulation procedure can be repeated, or additionalelectrodes can be successively (re)activated, until a sufficient ordesired level of therapeutic benefit occurs. For example, the patient'sneuropsychological stability may be adversely affected after severalmonths, such as 6 or 12 months, possibly due to an event in thepatient's life.

In several embodiments, a threshold signal intensity or levelcorresponding to a given electrode subset can be determined by applyingstimulation signals to this electrode subset, and measuring orestimating a minimum or near-minimum stimulation signal level that givesrise to a predetermined or minimum degree of change in neurocognitivetask performance. A treatment signal intensity or level that is appliedto the patient during a therapy period can be based upon a thresholdsignal level corresponding to one or more electrode subsets. Forinstance, a treatment signal level can be a given percentage of (e.g.,approximately 20-95%, or approximately 50%, 80%, or 90% of) theactivation threshold signal level corresponding to the particularelectrode subset that gave rise to the lowest threshold signal levelrelative to each electrode subset considered. The threshold level cancorrespond to a level (e.g., current level or voltage level) that causesaction potentials in a large enough portion of the target neuralpopulation to produce the patient function associated with the targetneural population. During a therapy period, a treatment signal can beapplied to the particular electrode subset that gave rise to this lowestthreshold level, and/or one or more other electrode subsets. In additionor as an alternative to the foregoing, a treatment signal intensity canbe a mathematical function such as an average or a weighted average of aplurality of threshold signal intensities, where in some embodiments aweighting function can prioritize a threshold signal intensityassociated with neurons in particular neural locations (e.g., moreanterior neurons) more heavily than a threshold signal intensityassociated with neurons within other (e.g., more posterior) neurallocations. In yet other embodiments, a treatment signal can be orinclude a set of pulses that are delivered approximately at or evenslightly above a threshold or expected threshold level.

Many of the foregoing embodiments include techniques for identifying atarget neural population, a target stimulation site, stimulationparameters, stimulation modalities, and/or suitable patients usingfunctional techniques, alone or in combination with techniques based onthe structure of the patient's brain. An expected advantage of thesetechniques is that they can more accurately identify characteristicsassociated with a stimulation therapy than can techniques that rely onbrain structure alone. In some cases, these techniques can eventually becorrelated with brain structures that are common from one patient to thenext and, in such cases, a practitioner can revert back to siteidentification and/or other parameter selection on the basis of one ormore structures that are defined with a new level of precision. In othercases, the foregoing techniques can continue to be used on apatient-by-patient basis to more accurately identify the stimulationcharacteristics.

From the foregoing, it will be appreciated that specific embodiments ofthe disclosure have been described herein for purposes of illustration,but that various modifications may be made in other embodiments. Forexample, the practitioner may use structurally based and/or functionallybased techniques that differ from those specifically described above.The practitioner may use more than two levels of information to identifytarget neural populations in at least some cases. In some cases, thepractitioner may produce an actual image upon which to base a parameterselection, and in other cases, at least some aspects of the parameterselection may be automated and/or may rely on the underlying data usedto produce the image without actually producing the image itself. Forexample, fractional anisotropy levels may be determined without the needfor an actual image, and regions of high tract density may be correlatedwith a location in space (referenced to a fiducial or anatomic feature)again, without the need for an actual image. The signals applied in anyof the foregoing methods can have a direct effect on the target neuralpopulation that lasts for as long as the signal is active, or along-term effect that can enhance, enable, augment and/or otherwisefacilitate the patient's natural neuroplastic responses. Such long termeffects can last for days, weeks, months or years after the stimulationhas ceased.

Several examples were described above in the context of depression, butthe same or generally similar methodologies can be used to address otherneuropsychiatric/neuropsychological conditions, including post-traumaticstress disorder (PTSD), eating disorders and others identifiedpreviously. In still further embodiments, the foregoing methods can beapplied to patients without disorders, e.g. to improve the cognitivefunctioning of a normal or above-normal patient. Many of the foregoingtechniques may be applied on a case-by-case basis that is specific toindividual patients. However, as discussed above, after a sufficientdatabase (e.g., group atlas) has been established as a result ofcollecting individual data, practitioners may in some cases be able tocircumvent certain steps over the course of time. For example,practitioners may find that for certain conditions (e.g., certain typesof depression), the same area of the DLPFC, (as identified by anatomicallandmarks), is always or nearly always a suitable target neuralpopulation.

Several examples were provided above with reference to specific brainareas (e.g., Brodmann areas 10 and 25) and/or specific loops (e.g.,thalamocortical loops). In other embodiments, similar techniques can beapplied to other areas. For example, when treating depression, theanterior cingulate cortex (ACC) may be identified as a non-superficialcomponent of the thalamocortical loop that also includes the DLPFC.Accordingly, target cortical neural populations may be selected on thebasis of tract density descending to the ACC.

Certain aspects of the invention described in the context of particularembodiments may be combined or eliminated in other embodiments. Forexample, aspects of the technique described in the context of FIG. 1 maybe combined with aspects of the technique described in FIG. 3. Further,while advantages associated with certain embodiments have been describedin the context of those embodiments, other embodiments may also exhibitsuch advantages and not all embodiments need necessarily exhibit suchadvantages to fall within the scope of the present disclosure.

1-25. (canceled)
 26. A method for treating a patient, comprising:identifying a patient as having depression; identifying a baseline levelof the patient's motor cortex excitability; for multiple areas of thepatient's DLPFC: applying stimulation to the patient's DLPFC using rTMStechniques; after applying stimulation to the patient's DLPFC,identifying a change in the patient's motor cortex excitability usingpaired-pulse TMS stimulation; based at least in part on identifiedchanges in the patient's motor cortex excitability for the multipleareas of the patient's DLPFC, selecting a signal delivery site;implanting at least one electrode proximate to the signal delivery site,within a cranial cavity of the patient's skull and outside a corticalsurface of the patient's brain; and reducing or eliminating patientdepression by preferentially directing electrical signals from the atleast one electrode to the signal delivery site.
 27. The method of claim26 wherein selecting a signal delivery site includes selecting thesignal delivery site to be at an area of the DLPFC that has a greatereffect on motor cortex excitability than other areas of the DLPFC. 28.The method of claim 26, wherein applying stimulation to the patient'sDLPFC includes applying stimulation for a period of about 20 minutes.29. The method of claim 26, further comprising repeating the process ofidentifying a change in the patient's motor cortex excitability and theprocess of selecting a signal delivery site during the course of thepatient's therapy to account for patient adaptation to the electricalsignals.